Porphyrins (a tetrapyrrolic system) have generated enormous interest as photosensitizers for the use in photodynamic therapy. Photofrin®, a hematoporphyrin derivative developed at Roswell Park Cancer Institute (RPCI) is currently being used all over the world for treating a variety of cancers. Some of the disadvantages of Photofrin are (i) prolonged skin phototoxicity and the patients are advised to stay away from direct sunlight at least for 4 to 6 weeks after the treatment, (ii) weak absorption at 630 nm limits its tissue penetration ability, therefore the deeply seated tumors are difficult to cure. Efforts are underway in various laboratories, including ours to develop more tumor avid compounds than Photofrin with reduced skin phototoxicity.
The utility has recently been shown of porphyrin-based compounds and “Bifunctional Agents” for nuclear imaging (PET/SPECT) and therapy or to determine the ability of tumor-avid photosensitizer as vehicles to deliver the desired imaging agent (e.g. fluorescence imaging, MRI) to tumor for “see and treat approach. The applicability of this approach in fluorescence imaging/PDT by using 3-(1-hexyloxyethyl)-3-devinyl-pyropheophorbide-a (HPPH, currently in Phase II human clinical trials) as a tumor-targeting moiety has recently been shown.
PDT is increasingly acceptable as a curative or palliative treatment of cancer and some non-cancerous conditions that are generally characterized by overgrowth of transformed cells. Interest in this procedure was promoted by the recent approval of PDT with Photofrin® (a complex mixture of hematoporphyrin derivatives) by regulatory health authorities in several countries for the treatment of lung, gastric, esophageal, bladder and cervical tumors, in addition to cervical dysplasia and actinic keratosis. A more detailed understanding of the mechanisms involved in the photosensitized damage of cells and tissues, and better definition of correlations between chemical structure and photodynamic activity for various classes of porphyrin compounds, led to the development of second-generation photosensitizers with improved phototherapeutic properties. Some of these photosensitizers have proved useful for non-oncological indications such as the wet form of age-related macular degeneration (AMD).1 
The successful outcome of PDT depends on the optimal interaction among three elements: light, photosensitizer and oxygen. In general, light in the red to near infrared region of the visible spectrum is outside the absorption bands of most endogenous absorbing molecules in human tissues. Consequently, the most frequently used PDT agents are porphyrins and their analogs (such as chlorins, bacteriochlorins and phthalocyanines) with absorption bands in the range of 630-800 nm. Recently, the availability of low-cost and compact red-emitting diode lasers that can be efficiently coupled with optical fibers, (allowing the irradiation of lesions in internal organs), has broadened the use of PDT.1 
Although the mechanism of porphyrin retention by tumors is not well understood, the balance between lipophilicity and hydrophilicity is recognized as an important factor. In our laboratory, on the basis of SAR and QSAR studies, we have been able to determine the important structural parameters in photosensitizers related to pyropheophorbide-a (660 nm),2 purpurinimides (700 nm)3 and bacteriopurpurinimides (800 nm)4. These compounds are currently at various stages of clinical and pre-clinical trials. In our previous work developing ‘dual-function’ agents for tumor imaging and PDT, we have shown that tumor-avid photosensitizers can be used as targeting vehicles to deliver imaging agents to tumors. This approach has been quite successful in preparing optical imaging/PDT5, PET imaging/PDT6 and MR imaging/PDT agents7. However, efforts are underway to improve the tumor-selectivity of these ‘bifunctional agents’.
In SAR studies with a series of alkyl- or aryl ether analogs of certain chlorins (ring D reduced) analogs, it has been observed that the (i) overall lipophilicity of the molecule and (ii) the presence of the substituent(s) at the variable peripheral position(s) of the molecule make a remarkable difference in tumor-uptake and PDT efficacy.
Previously in pyropheophorbide-a series (a chlorin system in which ring D is reduced), we synthesized and evaluated a series of alkyl ether analogs (e.g. compound 3 in Scheme 1, FIG. 7) for photosensitizing efficacy. We observed a parabolic relationship between the log P values (determines the overall lipophilicity of a compound) and the PDT activity and among these analogs the hexyl ether derivative (3a, HPPH) was found to be most effective. HPPH is currently under Phase II human clinical trials (Lung, Barrett esophagus and Head and neck cancer).
Recently, “Bifunctional Agents” for tumor imaging and PDT have been developed. Among a series of photosensitizers the iodobenzylether analog 5 exhibited excellent tumor imaging (PET imaging) and PDT efficacy.5 The initial results obtained from the preliminary in vivo screening also suggest the utility of this compound in imaging tumor metastasis. The initial results obtained from the comparative study with F-18 fluorodeozyglucose (F-18 FDG) showed the superiority of compound 5 over F-18 FDG. However a detailed study with higher species is currently in progress.
So far, most of the chlorins derived from chlorophyll-a analogs in our and other laboratories contain ring-D reduced system. In our previous inventions, we have shown that presence of positions of certain substituents at various peripheral positions in chlorins (ring-D reduced) makes a significant effect in PDT efficacy.